Clinical, Neuroimaging, and Metabolic Footprint of the Neurodevelopmental Disorder Caused by Monoallelic <i>HK1</i> Variants.

Wortmann, Saskia B; Feichtinger, Rene G; Abela, Lucia; van Gemert, Loes A; Aubart, Mélodie; Dufeu-Berat, Claire-Marine; Boddaert, Nathalie; de Coo, Rene; Stühn, Lara; Hebbink, Jasmijn; Heinritz, Wolfram; Hildebrandt, Julia; Himmelreich, Nastassja; Korenke, Christoph; Lehman, Anna; Leyland, Thomas; Makowski, Christine; Martinez Marin, Rafael Jenaro; Marzin, Pauline; Mühlhausen, Chris; Rio, Marlène; Rotig, Agnes; Roux, Charles-Joris; Schiff, Manuel; Haack, Tobias B; Syrbe, Steffen; Zylicz, Stas A; Thiel, Christian; Veiga da Cunha, Maria; van Schaftingen, Emile; Wagner, Matias; Mayr, Johannes A; Wevers, Ron A; Boltshauser, Eugen; Willemsen, Michel A

Clinical, Neuroimaging, and Metabolic Footprint of the Neurodevelopmental Disorder Caused by Monoallelic HK1 Variants.

Wortmann, Saskia B; Feichtinger, Rene G; Abela, Lucia; van Gemert, Loes A; Aubart, Mélodie; Dufeu-Berat, Claire-Marine; Boddaert, Nathalie; de Coo, Rene; Stühn, Lara; Hebbink, Jasmijn; Heinritz, Wolfram; Hildebrandt, Julia; Himmelreich, Nastassja; Korenke, Christoph; Lehman, Anna; Leyland, Thomas; Makowski, Christine; Martinez Marin, Rafael Jenaro; Marzin, Pauline; Mühlhausen, Chris; Rio, Marlène; Rotig, Agnes; Roux, Charles-Joris; Schiff, Manuel; Haack, Tobias B; Syrbe, Steffen; Zylicz, Stas A; Thiel, Christian; Veiga da Cunha, Maria; van Schaftingen, Emile; Wagner, Matias; Mayr, Johannes A; Wevers, Ron A; Boltshauser, Eugen; Willemsen, Michel A.

Afiliación

Wortmann SB; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Feichtinger RG; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Abela L; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
van Gemert LA; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Aubart M; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Dufeu-Berat CM; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Boddaert N; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
de Coo R; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Stühn L; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Hebbink J; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Heinritz W; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Hildebrandt J; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Himmelreich N; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Korenke C; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Lehman A; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Leyland T; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Makowski C; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Martinez Marin RJ; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Marzin P; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Mühlhausen C; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Rio M; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Rotig A; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Roux CJ; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Schiff M; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Haack TB; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Syrbe S; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Zylicz SA; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Thiel C; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Veiga da Cunha M; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
van Schaftingen E; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Wagner M; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Mayr JA; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Wevers RA; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Boltshauser E; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur
Willemsen MA; From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zur

Neurol Genet ; 10(2): e200146, 2024 Apr.

Article en En | MEDLINE | ID: mdl-38617198

ABSTRACT

ABSTRACT

Background and

Objectives:

Hexokinase 1 (encoded by HK1) catalyzes the first step of glycolysis, the adenosine triphosphate-dependent phosphorylation of glucose to glucose-6-phosphate. Monoallelic HK1 variants causing a neurodevelopmental disorder (NDD) have been reported in 12 individuals.

Methods:

We investigated clinical phenotypes, brain MRIs, and the CSF of 15 previously unpublished individuals with monoallelic HK1 variants and an NDD phenotype.

Results:

All individuals had recurrent variants likely causing gain-of-function, representing mutational hot spots. Eight individuals (c.1370C>T) had a developmental and epileptic encephalopathy with infantile onset and virtually no development. Of the other 7 individuals (n = 6 c.1334C>T; n = 1 c.1240G>A), 3 adults showed a biphasic course of disease with a mild static encephalopathy since early childhood and an unanticipated progressive deterioration with, e.g., movement disorder, psychiatric disease, and stroke-like episodes, epilepsy, starting in adulthood. Individuals who clinically presented in the first months of life had (near)-normal initial neuroimaging and severe cerebral atrophy during follow-up. In older children and adults, we noted progressive involvement of basal ganglia including Leigh-like MRI patterns and cerebellar atrophy, with remarkable intraindividual variability. The CSF glucose and the CSF/blood glucose ratio were below the 5th percentile of normal in almost all CSF samples, while blood glucose was unremarkable. This biomarker profile resembles glucose transporter type 1 deficiency syndrome; however, in HK1-related NDD, CSF lactate was significantly increased in all patients resulting in a substantially different biomarker profile.

Discussion:

Genotype-phenotype correlations appear to exist for HK1 variants and can aid in counseling. A CSF biomarker profile with low glucose, low CSF/blood glucose, and high CSF lactate may point toward monoallelic HK1 variants causing an NDD. This can help in variant interpretation and may aid in understanding the pathomechanism. We hypothesize that progressive intoxication and/or ongoing energy deficiency lead to the clinical phenotypes and progressive neuroimaging findings.

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Neurol Genet Año: 2024 Tipo del documento: Article